Vol. 29, Issue 7, 976-982, July 2001

SHORT COMMUNICATION
Metabolism of Norethisterone and Norethisterone Derivatives in Rat Uterus, Vagina, and Aorta

M. J. Blom, M. Groot Wassink, F. van Wijk, A. G. H. Ederveen, H. J. Kloosterboer, C. H. J. Verhoeven, J. G. D. Lambert, and H. J. Th. Goos

University of Utrecht, Research Group for Comparative Endocrinology, Graduate School for Developmental Biology, Utrecht, The Netherlands (M.J.B., M.G.W., F.v.W., J.G.D.L., H.J.Th.G.); and Organon NV, Oss, The Netherlands (A.G.H.E., H.J.K., C.H.J.V.)

The 19-nor-progestogen norethisterone is used as a progestogen component in contraceptives and in continuous- and sequential combined hormone replacement therapy (HRT) in postmenopausal women. Metabolism of norethisterone in HRT target tissues may play a role in its biological response. The aim of this study was to investigate which steroid-metabolizing enzymes are present in rat uterus, vagina, and aorta, three HRT target tissues. Next, the ability of the tissues to metabolize norethisterone was assessed. Furthermore, to investigate the effect of substituents at the 7- and 11-position, the metabolism of Org OM38 (7-methyl-norethisterone), Org 4060 (11-ethyl-norethisterone), and Org 34694 (7-methyl,11-ethylidene-norethisterone) was studied. Using radiolabeled progesterone, the presence of 20-hydroxysteroid dehydrogenase, 5-reductase, and 3-hydroxysteroid dehydrogenase activity could be demonstrated in uterus, vagina, and to a lesser extent in aorta. The combined action of the latter two enzyme activities resulted in 3-OH,5-H-norethisterone as the major metabolite of radiolabeled norethisterone in uterus (26.9%), vagina (37.1%), and aorta (1.4%). The norethisterone derivatives, however, were metabolized to a much lesser extent (1.0-7.6%). No formation of 5-reduced forms of Org 4060, Org OM38, or Org 34694 was found, while formation of minor amounts of 3-OH-Org 4060 and 3-OH-Org OM38 could be demonstrated in both uterus, vagina, and aorta. These findings confirm the role of 5-reductase as a rate-limiting step in the metabolism of norethisterone derivatives and show important inhibitory effects of substituents at the 7- and 11-position of the steroid skeleton on 5-reduction.